Chemical Biology to Modulate PCSK9 and Treat Atherosclerosis
John Chorba, Professor
UC San Francisco
Closed. This professor is continuing with Fall 2024 apprentices on this project; no new apprentices needed for Spring 2025.
PCSK9 chaperones the low-density lipoprotein receptor (LDLR) to the lysosome for degradation, thereby raising circulating LDL (i.e. “bad” cholesterol) and accelerating atherosclerosis and heart disease. Despite its validation as a drug target, PCSK9 has proven difficult to drug with small molecules, at least in part because of its single-turnover protease activity. We have solved this problem by amplifying protease readout in cell-based assays and have used our solution to find novel molecular scaffolds that inhibit PCSK9 function and increase LDL receptors in hepatic cells. These results mimic the functional outputs of the most highly successful clinical therapies against heart disease. We aim to develop these compounds as both precursors to new cholesterol-lowering therapies and as chemical probes to further elucidate PCSK9’s role in both normal cell biology and disease. In parallel, we use cutting-edge forward genetics screens to understand the molecular details of PCSK9's mechanism of effect.
Role: Key laboratory tasks can include:
- Cloning and expression of engineered proteins
- Biophysical studies of pertinent compounds
- Medicinal chemistry to develop analog PCSK9 probes
- Development of PCSK9-mutant cell lines
- Development of reporter assays to assess PCSK9 uptake
- In vivo models of PCSK9 perturbation
The student will work collaboratively with the lab to develop gradually increasing levels of independence to identify a sub-project of which they can take ownership.
Qualifications: Basic knowledge of molecular biology, cell biology, organic chemistry, and biochemistry. More important than any particular technical skill is the drive to learn and develop independent thinking.
Hours: to be negotiated
Related website: https://chorbalab.ucsf.edu/
Biological & Health Sciences